Incidence of serious infections in the working-age Japanese adult population with rheumatoid arthritis treated with tumor necrosis factor-α inhibitors and interleukin-6 inhibitors: A nationwide retrospective cohort study.

AIM: This retrospective cohort study aimed to compare the risk of serious infections in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor-α inhibitors (TNFαi) and interleukin-6 inhibitors (IL-6i), with no prior use of biological disease-modifying antirheumatic drugs (bDMARDs). METHODS: We employed the nationwide insurance claims database encompassing the years 2005 to 2018 in Japan. The inclusion criteria specified patients who were prescribed any type of bDMARDs, including TNFαi and IL-6i. The following exclusion criteria were applied: missing prescription dates, RA not diagnosed, below 16 years of age, bDMARDs prescribed within 6 months of registration, RA diagnosed post-bDMARDs prescription, and incidence of serious infections within 2 weeks before bDMARDs therapy. We applied stabilized inverse probability weights and utilized a Cox regression model to estimate the risk of serious infections associated with TNFαi and IL-6i. RESULTS: The cohort of 2493 patients with RA was categorized into a TNFαi group and an IL-6i group of 2018 and 475 participants, respectively. The median follow-up duration (interquartile range) was 347 (147-820) days in the TNFαi group and 369 (149-838) days in the IL-6i group. In the inverse probability-weighted cohort, the incidence rates (95% confidence interval) of serious infections were 2.13 (1.65-2.71) and 3.25 (2.15-4.69) per 100 person-years for the TNFαi and IL-6i groups, respectively. The hazard ratio (95% confidence interval) comparing the TNFαi group to the IL-6i group was 0.66 (0.36-1.20, p = 0.168). DISCUSSION: The results underscore the lack of evidence to preferentially favor either TNFαi or IL-6i as later-line therapy in the management of bDMARDs-naive RA to mitigate the risk of serious infections.

Predictors of olaparib discontinuation owing to adverse drug events in patients with ovarian, peritoneal, or fallopian tube cancer: a retrospective observational study.

We investigated predictors of olaparib discontinuation owing to adverse effects. Patients with ovarian, peritoneal, or fallopian tube cancers treated with olaparib at Osaka Medical and Pharmaceutical University Hospital between April 2018 and September 2022 were included in this study. The exclusion criteria were as follows: discontinuation of treatment due to disease progression, use of anaemia medications, and use of cytochrome P450 (CYP3A4) inhibitors. The follow-up period was 90 d. Of the 46 eligible patients, 21 patients discontinued olaparib, including 15 patients with grade 3 or higher anaemia, eight patients with grade 3 or higher neutropenia, and four patients with non-haematological toxicity (including multiple onset). Multivariate logistic regression analysis showed that grade 4 neutropenia and anaemia progression to grades 2-3 due to chemotherapy administered before olaparib administration were predictors of olaparib discontinuation. The severity of neutropenia and anaemia due to chemotherapy before olaparib administration may be a potential marker for its discontinuation.

Platelet count and dose, but not comorbidities, predict severe neutropenia in cabazitaxel-treated prostate cancer patients: A retrospective observational study.

OBJECTIVE: To determine the safety of cabazitaxel and predictors of severe neutropenia caused by cabazitaxel in a patient population that includes those with comorbidities. MATERIALS AND METHODS: Of 42 prostate cancer patients treated with cabazitaxel at Osaka Medical and Pharmaceutical University Hospital between September 2014 and June 2022, 33 were included in this study, whereas 6 patients who were outpatients and 3 who were discharged early within 7 days upon patient request were excluded. Logistic regression analysis was used to examine predictors of severe neutropenia. RESULTS: Of the 33 eligible patients, 24 had comorbidities, with hypertension being the most common (n = 19), followed by dyslipidemia (n = 14) and diabetes (n = 11). There was no statistically significant difference in the rate of severe neutropenia due to any of the comorbidities, depending on the presence or absence of the comorbidity. However, the rate of severe neutropenia was significantly higher in patients with baseline platelet levels < 22.4×104/µL and those receiving cabazitaxel doses > 34 mg/body. In the final model adjusted for age, body mass index, C-reactive protein, and monocyte count, lower baseline platelet levels and higher doses of cabazitaxel were also predictors of the development of severe neutropenia. CONCLUSION: Comorbidities such as hypertension, dyslipidemia, diabetes mellitus, cerebrovascular disease, chronic kidney disease, liver dysfunction, and cardiac disease did not affect the incidence of severe neutropenia in patients receiving cabazitaxel. The baseline platelet count and the dose of cabazitaxel were also suggested to be markers for the development of severe neutropenia.

Disproportionality analysis of acetaminophen-induced hepatic disorders with and without immune checkpoint inhibitors.

BACKGROUND: Although acetaminophen is recommended for the treatment of mild-to-moderate cancer pain, acetaminophen-induced hepatic disorders pose an important clinical challenge. Concomitant prescription of immune checkpoint inhibitors (ICIs) may further increase the risk of hepatic disorders in patients taking acetaminophen; however, there are few clinical studies that confirm this. AIM: To evaluate the risk of hepatic disorders in patients taking concomitant acetaminophen and ICIs using a disproportionality analysis from the Japanese Adverse Drug Event Report database. METHOD: Acetaminophen users aged ≥ 20 years were included; factors that can affect the risk of acetaminophen-induced hepatic disorders were collated. Similar data on the widely used analgesic, loxoprofen, were used for comparison. RESULTS: Among 233,594 patients surveyed, 10,403 were prescribed acetaminophen, and among them, 1,245 patients developed hepatic disorders. The disproportionality of hepatic disorders was observed in acetaminophen users regardless of concomitant ICI use (without ICI: reporting odds ratio [ROR], 1.18; 95% confidence intervals [CI], 1.10-1.26; with ICI: ROR 1.87, 95%CI 1.59-2.20); it was even higher in concomitant acetaminophen and ICI users (ROR 1.94, 95%CI 1.65-2.29). However, increased disproportionality of hepatic disorders was not observed in patients taking concomitant loxoprofen and ICI. Multivariable logistic regression showed that the risk of hepatic disorders in acetaminophen users was associated with concomitant use of ICI (ROR, 1.91; 95% CI, 1.49-2.45); (P < 0.01). CONCLUSION: Our findings suggest that the risk of hepatic disorders is greater with concomitant acetaminophen and ICI treatment than with acetaminophen alone.

Preventive effect of dexamethasone premedication on the development of infusion-related reaction in breast cancer patients receiving trastuzumab.

AIM: To clarify the incidence and risk factors of infusion-related reactions (IRRs) caused by trastuzumab in breast cancer patients and verify the preventive effects of dexamethasone. METHODS: All breast cancer patients newly treated with trastuzumab at the Osaka Medical and Pharmaceutical University Hospital from 1 January 2017 to 31 December 2020 were included. The electronic medical records were retrospectively reviewed. The outcome measure was the occurrence of IRRs of grade 1 or higher during trastuzumab infusion. Only dexamethasone and anticancer drugs administered concomitantly before trastuzumab were used as explanatory variables. RESULTS: The 176 patients included in the study received 2320 infusions. Fifty-eight patients (33.0%) experienced IRRs, and IRRs occurred in 80 (3.4%) of the total 2320 infusions. Owing to the hierarchical structure of the data, the independence of the observed values was evaluated using the intraclass correlation coefficient. Multivariate multilevel logistic regression analysis showed that premedication with dexamethasone lowered the risk of trastuzumab-induced IRRs (mg, per 1 unit, odds ratio [OR] = 0.61, 95% confidence interval [95% CI] 0.43-0.85, P = .003). In addition, preoperative status (OR = 38.9, 95% CI 5.4-278.7, P < .001) and high-dose trastuzumab (mg/kg, per 1 unit, OR = 60.6, 95% CI 20.1-182.9, P < .001) were independent risk factors for IRRs. CONCLUSION: The results of this study suggest that premedication with dexamethasone exhibits preventive effects on trastuzumab-induced IRRs in breast cancer patients. Future studies are needed to determine the optimal dose of dexamethasone to prevent IRRs and the impact of dexamethasone on the efficacy of trastuzumab in breast cancer.

Biologic Disease-Modifying and Other Anti-Rheumatic Drugs Use in Patients with Moderate-to-Severe Juvenile Idiopathic Arthritis Based on a Japanese Nationwide Claims Database.

Purpose: Biologic disease-modifying anti-rheumatic drugs (bDMARDs) are highly effective and safe against juvenile idiopathic arthritis (JIA), which is classified into systemic JIA (sJIA) and the other JIA categories (non-sJIA) according to differences in clinical symptoms and pathophysiology. The purpose of the current study was to investigate trends in patterns of prescribing bDMARDs for moderate-to-severe JIA using a relatively large sample size in Japan. Patients and Methods: A descriptive epidemiological study based on a nationwide claims database in Japan was conducted from 2012 to 2018 using the "JMDC Claims Database" to explain annual changes based on the number of patients prescribed bDMARDs. Study drugs were identified based on the Anatomical Therapeutic Chemical codes, such as methotrexate, glucocorticoids, non-steroidal anti-inflammatory drugs, and bDMARDs. Results: From a database of 6,862,244 patients, the following exclusion criteria were applied: aged ≥16 years, without "M08" in their ICD-10 code as disease, and missing the information of prescription date in the database during the study period, resulting in a final number of 111 JIA patients. We found an increasing trend for adalimumab and tocilizumab and a decreasing trend for methotrexate. Differences in medication use between sJIA and non-sJIA patients were also evident, being consistent with national and international guidelines. Conclusion: Although the introduction of bDMARDs has markedly improved the efficacy of JIA therapy, there are still many short- and long-term safety issues to be examined, including the risk of infection and potential risk of associated malignancy. Future studies are needed to clarify these issues.

The Relationship Between Duration of General Anesthesia and Postoperative Fall Risk During Hospital Stay in Orthopedic Patients.

OBJECTIVES: We performed a retrospective observational study to investigate the relationship between general anesthesia duration and postoperative falls of hospitalized patients who underwent orthopedic surgery. METHODS: We used electronic medical record data and incident report data from the Osaka Medical and Pharmaceutical University Hospital. The study included 4,042 patients admitted to the Department of Orthopedic Surgery from 2014 to 2018, and the following exclusion criteria were applied: no surgery, less than 18 years of age, and fall between admission and surgery. This study only considered falls that occurred within 21 days of surgery. The multivariate logistic regression model adjusted for patient background was used to determine the risk of falling according to the duration of general anesthesia. RESULTS: After exclusions, 3,398 patients were included in the analysis. Among them, 45 patients (1.32%) had fallen, of whom 7 (15.6%) were injured and 2 (4.4%) experienced fractures. Multivariate logistic regression analysis to determine the adjusted odds ratio showed that longer general anesthesia duration was an independent risk factor for postoperative falls. In addition, cardiovascular disease had significantly higher associations with postoperative falls. CONCLUSIONS: In the postoperative care of orthopedic patients, the risk of falling should be assessed by considering the duration of general anesthesia in addition to the traditional fall risk factors. Furthermore, falls could be prevented by educating patients and their caregivers about the risk and mobilizing staff to support postoperative patients at a higher risk of falls when they walk in the hospital.

Safety profile of clozapine: Analysis using national registry data in Japan.

Clozapine is the only effective antipsychotic drug used for the treatment of treatment-resistant schizophrenia. Although it has been shown that the frequency of clozapine use is very low in Japan, our previous study revealed that the number of clozapine prescriptions has been increasing in recent years, and that risk factors leading to discontinuation of clozapine were also identified as age ≥40 years, poor tolerability to olanzapine, previous treatment with clozapine, and white blood cell count <6000/mm3. The main cause for discontinuation of clozapine is the occurrence of a wide range of adverse events, including neutropenia/leukopenia and fatal cardiac disorders. In this study, we analyzed the physical details and backgrounds of patients with adverse events that led to clozapine discontinuation using a national registry database of more than 8000 Japanese patients. The physical adverse events that led to discontinuation of clozapine were neutropenia/leukopenia, glucose intolerance, cardiac disorders, gastrointestinal disorders, neuroleptic malignant syndrome, pleurisy, pulmonary embolism, sedation/somnolence, and seizures. Neutropenia/leukopenia had the highest incidence (5.0%). Neutropenia/leukopenia and cardiac disorders tended to occur early in the treatment period, indicating the need for careful monitoring for these adverse events in the early stages of clozapine treatment. Gastrointestinal disorders occurred over a long period of time, suggesting the need for careful observation during the maintenance period. The data obtained in our study will lead to the optimal and safe use of clozapine treatment.

Safety of Ramucirumab Regimen Without H1-antihistamine Premedication in Patients With Solid Cancers.

BACKGROUND/AIM: To prevent infusion-related reactions (IRRs), H1-antihistamines (H1AT) are recommended as a premedication for monoclonal antibodies, such as Ramucirumab (RAM), even though there are H1AT-related side effects, such as drowsiness and dizziness. Here, we investigated the safety of H1AT-free RAM regimens in patients with solid cancer. PATIENTS AND METHODS: We retrospectively reviewed the patients with solid cancer receiving RAM without H1AT at Osaka Medical College Hospital between 2015 and 2019. RESULTS: Among the 123 registered patients, 58 were identified as eligible. The total number of RAM infusions was 291, and the median number of RAM administration was 4 cycles (range=1-23 cycles). IRRs were not observed in any patient. CONCLUSION: Although our data are preliminary and limited, H1AT-free RAM regimens may be a treatment option for cancer patients having a significant risk of developing H1AT-related side effects. Further studies are needed to confirm the safety of H1AT-free RAM regimens.

What can predict and prevent the long-term use of benzodiazepines?

Although benzodiazepines (BZDs) are commonly prescribed for insomnia or anxiety, long-term use of BZDs causes serious adverse effects such as daytime drowsiness and cognitive decline. In the current study, we evaluated the predictors and preventers of long-term usage of BZDs from a retrospective survey by utilizing the 12-year prescription record of a university hospital. From the prescription data of 92,005 people, users of BZDs (n = 3,470, male = 39.2%, mean age = 60 ± 17.5) were analyzed. During this period, both the number of prescriptions (2722 in 2004 to 1019 in 2016) and the number of BZDs (1.73 in 2004 to 1.36 in 2016) gradually decreased, although more than half of the patients continued to take BZDs for over three years. High risk factors for long-term use of BZDs include elderly patients (>65 years old), high dosage (>5 mg diazepam per day), psychiatrist-prescribers, and users with polytherapy. Discontinuation is significantly found in users of hypnotic BZDs and alternative psychotropic medical drugs (including antipsychotics, serotonergic drugs, or newer types of sleep medicine). Future studies should focus on elucidating interventions that are more effective against long-term usage of BZDs.

[Influence of the Site of Port Insertion on the Flow Velocity of 5-FU Continuous Intravenous Injection by Using a Compression-Type Portable Continuous Infuser for Colorectal Cancer Patients].

For the continuous intravenous injection off luorouracil (5-FU) over 46 hours in a chemotherapeutic regimen for colorectal cancer, a compression-type portable continuous infuser is used. However, there is an error in the flow velocity. Errors in the dose or time of administration completion may influence the efficacy and safety of 5-FU. Therefore, it is necessary to reduce the error in the flow velocity. The type of diluent, air temperature, and concentration of 5-FU are reportedly factors influencing the flow velocity. However, no study has examined the influence of the site of port insertion. In this study, we investigated factors associated with the flow velocity of 5-FU continuously and intravenously injected by using an infuser in patients with colorectal cancer, among whom the site of port insertion differed. The results showed that the site of port insertion influenced the flow velocity during the continuous intravenous injection of 5-FU using an infuser. It is important to reduce the error in the flow velocity by considering the site of port insertion in addition to the concentration of 5-FU and the air temperature.

[Effectiveness of intervention by the infection control team for cancer patients with a positive blood culture].

Cancer patients at a high risk of acquiring infectious diseases should be maintained in a facility where good infection control practices are followed. At our hospital, the infection control team(ICT)provides expertise, education, and support to the staff, helping them maintain proper standards, thereby minimizing the risks of infection. The ICT(established in 2004)has implemented infection control programs by employing an appropriate number of staff members after the revision of medical treatment fees in 2011. Our intervention program includes 2 general policies, namely, ordering and collection of blood cultures and intervention for the medical care of patients with positive blood cultures. In this study, we evaluated the effectiveness of our intervention for cancer patients with a positive blood culture. During the surveillance period(April 2011 to July 2012), 42 positive cases were determined to be infectious. ICT intervention was required in 37 cases. Our suggestions were accepted in 92%(34/37)of the cases, and improved outcome was estimated in 65%(22/34)of the cases. The results of our study contribute to the scientific bases on which routine clinical practices could be promoted in the future.

[Serotonin syndrome in a patient with small cell lung cancer].

The patient was a 67-year-old male who had been treated for several years with 150 mg fluvoxamine maleate due to depression. He visited our hospital with primary symptoms of swelling of the right upper extremity and dyspnea in August, XXXX. As a result of examinations, he was diagnosed with stage IIIB extended small cell lung cancer(T4N3M0). One course of carboplatin/etoposide(CBDCA/VP-16)therapy was started on October 1. Since the tumor size was reduced, thoracic effusion disappeared, and superior vena cava syndrome was alleviated, the therapy was changed to cisplatin/irinotecan (CDDP/CPT-11)on October 23, and the 3rd course was initiated on November 22. Anxiety and tremor appeared on the 4th day of the 3rd course and because they were exacerbated, and myoclonus appeared, a diagnosis of serotonin syndrome was made on the 38th day, and the administration of fluvoxamine maleate was discontinued. The symptoms were alleviated after the discontinuation, and the 4th course could be implemented. In this patient, serotonin syndrome was considered to have been induced by serotonin secretion promoted by the CDDP administration, and by serotonin in the brain increasing abnormally due to the SSRI.

[Comparison of chemotherapy side effects between elderly and young subjects].

UNLABELLED: With the aging of society, the number of elderly patients receiving chemotherapy has increased. Since organ function, particularly the liver and kidney function, is known to decrease with age, there is concern that severe side effects may develop in the elderly because of chemotherapy. It is a considerable challenge to establish safe, effective chemotherapy that enables elderly patients to maintain a favorable QOL. Therefore, we conducted a survey of the current status of chemotherapy side effects. METHODS: The subjects were patients enrolled in physician-led clinical trials between April 2006 and December 2010. A survey of the chemotherapy regimens used, PS, and, side effects(CTC-AE v3.0)was conducted to examine differences in the incidence and Grade of side effects between elderly and younger subjects(aged 65 years or older, and younger than 65 years, respectively). The subjects consisted of9 3 elderly and younger people, with mean ages of 70 and 59. 5 years, respectively. Myelosuppression of Grade 3, or more severe side effects in the elderly and younger subjects, was 22. 5% and 16. 3%, respectively. The incidence of side effects was slightly higher in the elderly than in the younger subjects. In general clinical practice, side effects are controlled by selecting regimens and adjusting doses for the elderly. However, in clinical trials in which the dosage is predetermined regardless of age, the elderly are more prone to develop side effects than young people. We compare and present the current status regarding the side effects, effectiveness, and contents of chemotherapy regimens.